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Balancing Paradigms with Mesenchymal Stromal Cells

Steve Gschmeissner/Science Photo Library

Innovation isn't uniquely devoid of commonality of adoption by discipline. Rather the likelihood of acceptance generally tracks evenly to historical norms in parallel with society's openness to progress and the search for solutions. However, the impact of technological change is variable and dependent on societal factors related to income and health. One could argue the greatest benefit comes when change drives both economic prosperity and improved health standards. While the average pace of technological innovation slowed some decades ago the recent rapid rise of medical science has taken on the mantle of sustainability for growth. The dramatic impact potential of fundamentally transformative practices in healthcare is being fueled by access to new knowledge and a greater sharing of insight. Today, due to the convergence of various technology led disciplines, there are many important catalysts for paradigm shifting change. A key criteria common to all are the Drivers - fundamental products or processes that opens up the gates to new realms of understanding and acceptance. At each juncture a bridge must span the divide and a stake ground into new terrain. Are MSCs a Driver that can forge a paradigm shift in stem cell healthcare & how did we get here?

The investigation of bone marrow (“BM”) stem cells led to the establishment and widespread clinical practice using cells of the mesodermal blood lineage via bone marrow transplantation – known as hematopoietic cells (“HSCs”).

The first use of these BM stem cells as therapy was pioneered over 50 years ago when transplants were first introduced experimentally to treat leukemia. However, as with most donor tissue the understanding of immune rejection of foreign non-self cells was and still is of major concern for the successful treatment of disease using allogeneic (donor) tissue. This is even the case when immuno-histocompatibility is done via matching of the cells to the host. This complication has stymied the field of cellular therapeutics due to the severe adverse events that can result from the administration of donor derived cellular treatments. In the case of BM transplantation they routinely cause Graft versus Host Disease (“GvHD”) as a result of the treatment, with approximately 50% of all such patients reporting complications. The percentage of mortality as a result of this last resort treatment intervention even today is staggering with up to 17% of all severe liver/gut GvHD cases resulting in death(1).

NIH.gov

As a field the discovery and isolation of Mesenchymal Stromal Cells (“MSCs”), a small subset of BM niches representing less than 0.01% of all HSCs, was a watershed moment. It was a true breakthrough as these cells were found to be able to replicate as multipotent precursors and can be differentiated into fat, bone and cartilage. The isolation and clonal nature of these MSCs opened up a whole new avenue for cellular investigation. Further sources of MSCs were discovered in a range of bodily tissues, including fat, perinatal tissue and dental pulp. The technology for human application of these adult cells gave rise to the stem cell industry we know today. Upwards of 500+ clinical trials using MSCs are registered currently in the US central database clincaltrial.gov for a variety of unmet disease indications (2).

In addition, there is a large growing trend of undocumented cases using MSC products in private medical offices as marketed treatments via autologous (self-to-self) therapies (3). These unlicensed medical practitioners using MSCs products are the subject of considerable debate as to where the line should be drawn between required regulatory oversight and freedom of medical use in private clinics for autologous treatments. The US FDA is currently reviewing draft guidelines (4,5,6,7) for treatment products using MSCs. They are preparing to define what constitutes more than minimal manipulation and cell use parameters. This is with a view to determining clinical trial requirements for MSC biologics, in keeping with current drug development procedures already in place.Safe and Effective?

The prospect of MSC utility for therapeutics has been due in large part to the evident immunological privileged nature of MSCs and their potential for universal application without immunosuppressive drugs – unlike HSCs themselves. Although MSCs have an antigen profile they lack major class antigens which makes them relatively immune-privileged to the host system thereby allowing for donor derived cell treatments without treatment rejection in low dose regimes.

The Scientist - Keith Kasnot

The properties of MSC have been appropriately described as “ambulatory” and “paramedic” – i.e. they’re built to respond to injury in the body and assist in its repair. How they detect, migrate and signal, in addition to what biological manner they act, and what way in different circumstances, is a source of considerable study. It seems clear though now that their “method of action” (“MOA”) is modulatory in nature via complex regulatory mechanisms (8). One such mechanistic attribute is via the excretion of bioactive factors (vesicles, exosomes et al) and work to facilitate cell to cell communication networks (9).

Much has been written about the potential of tissue derived MSCs as a treatment option for a host of acute, immune and degenerative conditions. However, the field is still developing and protocols are being tested and adjusted to maximize possible outcomes. I’ve added an overview video below on the challenges and issues faced by MSCs product developers’ to-date by a leading expert in the field Dr. Jacques Galipeau of Emory University. The presentation highlights a number of findings on research and data in this sector and is well worth watching

Dr. Jacques Galipeau of Emory University

As mentioned, and referred to in the video, numerous clinical studies are underway on the use of MSCs and case reports have been published on both the potential benefits and in certain cases a lack of statistical benefit in patients receiving these cells from a variety of tissue sources.

With regard to the clinical trial results there is clear validation of MSCs safety profile, which is fundamental to their successful translation. Potential treatment efficacy of MSCs is suggestive to-date of positive activity on various outcome measures in a number of reported studies. These positive results are counter-balanced with questions on method of action (“MOA”) and some failed studies. This somewhat mixed picture generally points to issues relating to the development of medicinal products and cellular biologics should be viewed as no different.

A few of the better known company examples of MSC sector developments in the sector are briefly summarized below with links to the company for further details on the data.

TiGenix (adipose/fat) – has moved on from the 1st EU approved and marketed autologous (“auto”) MSC cell therapy called ChrondroCelect for cartilage repair to an allogeneic (“allo”) product strategy with solid Phase III results in hand for Cx601 in Crohn’s Disease. This will mark their first allo indication nearing approval with other adipose stem cell products in the pipeline.

Mesoblast (BM) – bought the first approved western auto cell therapy Prochymal for GvHD from Osiris which had mixed results and was never released. They are developing a full in-house line-up of allo product candidates with good support data and are partnered with a Teva Pharma. Notable pipeline news include marketing approval of TemCell in Japan for GvHD with local partner JCR Pharma (repackaged Osiris product) and solid data in late stage trials (MSC-100-IV for GvHD also, MPC-150-IM for heart and MPC-06-ID for back pain, amongst others).

Athersys (BM) – lost Pfizer as a program partner for MultiStem after releasing mediocre data in ulcerative colitis. A second Phase II read-out, this time in stroke, also failed to meet endpoints. However, newly released interim data in its ongoing stroke study is now suggestive of positive results from the homing-in strategy on potential earlier treatment window benefit. Also of note are the additional clinical programs in development for cardiovascular and inflammatory/immune indications. In addition there’s a solid validation deal with Healios of Japan for MultiStem in that market and use of the product for Healios’ ongoing development programs.

Vericel (BM for heart program) – previously known as Aastrom with a long history of development of auto MSCs for heart and CLI indications with poor accumulated data continues to develop the heart product in clinical studies with recent positive data after previous endpoint failure, indicative of statistical benefit. In 2014 they secured additional auto cell therapy products from Sanofi (Carticel & MACI – cartilage and Epicel – skin) which had previously received certain market authorizations and are generating revenue with patient benefit.

Indicative data sets for comparative analysis and ratio breakout are yet to be tabulated with regard to which conditions and methodologies the cells work well for and in which cases they don’t help all that much or at all. However, one must be cautious when assessing the efficacy value of cellular products as they are biologics and there are many issues relating to their degree of effectiveness, such as: their source; derivation method; inherent donor variability; passage potency; culture conditions & scale-up manufacturing; cold chain methodology; target indication; patient population; disease states and application methods, amongst others. As a result not all cellular products will perform well in human studies. These issues play a significant role in whether they achieve benefit in tests on patients, and to what extent in relation to standard of care. Although the jury is still out there is a general agreement based on empirical data that these cells are on the whole safe, when developed and used appropriately. Where they have been shown to have positive outcome and biological activity there is acknowledged room for improvement with regard to enhancing efficiency, potency and cell mechanistic action, which is encouraging.

One aspect of the development of industrial scale cellular therapies speaks to the need for increased replicative capacity, lower passaged products and standardization via use of optimization technologies and shifting to pluripotent cell sources instead of donor derived batch processing of multipotent cells.

As a result of this progressive development culture method adjustments gleaned from the early pioneering work of MSC development are giving rise to efficiencies of process and improved manufacturing protocols for next generation methods in both multipotent and pluripotent products. The above mentioned early leaders in MSC product offerings are beginning to line up their treatments for entry to the market, while the sector looks to prepare and trial the more advanced cell factories of the future.

This momentum is also being driven by the rise of synthetic constructs using MSCs - the personalized tailoring of targeted medicines for improved performance. MSCs possess inherent homing and immunomodulatory properties and therefore are ideal for use in combination with gene and nano technologies. In addition, the extraction of the inherent cell properties of MSCs for standalone biologic products adds to the overall picture and excitement in the field.

MSC products are representative of the wider cell therapeutic field and are the standard bearers in the effort to bridge the shifting paradigms of new treatment modalities for patients in need.